title: Why do so many drugs for Alzheimer's disease fail in development? Time for new methods and new practices?
abstract: Alzheimer's disease (AD) drug developments and clinical trials (CT) remain vulnerable to problems that undermine research validity. Investigations of CT methods reveal how numerous factors decrease active drug-placebo group differences and increase variance, thereby reducing power to reach statistical significance for outcome measure differences in AD CTs. Such factors include, amongst many, inaccuracy, imprecision, bias, failures to follow or lack of operational protocols for applying CT methods, inter-site variance, and lack of homogeneous sampling using disorder criteria. After a review of the literature and survey of a sample of AD and Mild Cognitive Impairment (MCI) CTs, the authors question whether problems of human error preclude AD researchers from continuing their dependence on rated outcome measures for CTs. The authors propose that the realities of AD, especially a probable irreversible progression of neuropathology prior to onset of clinical symptoms or signs capable of differentiating persons at risk for AD from normal aged, require AD investigators and clinicians to privilege biomarkers and encourage their development as surrogate targets for preventive AD treatment developments, testing, and use in clinical practice.
authors.affiliation: Drug Design & Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA. rebecker2008@comcast.net
authors.forename: Robert E
authors.initials: RE
authors.lastname: Becker
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Greig
authors.forename: Ezio
authors.initials: E
authors.lastname: Giacobini
mesh_terms: D000544:Alzheimer Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000523:psychology; D000818:Animals; D015415:Biomarkers; D002986:Clinical Trials as Topic; D006801:Humans; D015588:Observer Variation; D018579:Patient Selection; D011619:Psychotropic Drugs / Q000008:administration & dosage / Q000627:therapeutic use*; D011643:Publishing; D015203:Reproducibility of Results; D012107:Research Design; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D011619:Psychotropic Drugs